Prolactin Receptor
Identifiers
SymbolPRLR
NCBI gene5618
HGNC9446
OMIM176761
PDB1RW5
RefSeqNM_000949
UniProtP16471
Other data
LocusChr. 5 p13-p12
Search for
StructuresSwiss-model
DomainsInterPro

The prolactin receptor (PRLR) is a type I cytokine receptor[1] encoded in humans by the PRLR gene on chromosome 5p13-14. It is the receptor for prolactin (PRL). The PRLR can also bind to and be activated by growth hormone (GH) and human placental lactogen (hPL). The PRLR is expressed in the mammary glands, pituitary gland, and other tissues. It plays an important role in lobuloalveolar development of the mammary glands during pregnancy and in lactation.

Structure

The prolactin receptor (PRLR) is a membrane-bound protein of the cytokine receptor superfamily. In humans, it is encoded by a single gene which contains 11 exons and is located on chromosome 5.[2] PRLR expression can be found in several tissues such as the gonads, breast, uterus, heart, liver, kidney, brain, immune cells, as well as adrenal and pituitary glands.

Several PRLR isoforms have been described in different tissues. These have varying lengths and cytoplasmic domain composition, but share identical extracellular domains, which are the regions binding to PRLR.

Diversity of PRLR is a result of transcription initiation in different sites of the PRLR promoter region. Additionally, post-translational modifications, like alternative splicing are the events that result in the different isoforms that allow for all the different actions of prolactin in the body.[3]

Signaling

The PRLR is a class 1 cytokine receptor that uses messenger pathways to control cell proliferation, migration, intracellular ion concentration and inhibit programmed cell death (apoptosis).[4][5] PRLRs also have functions in the second messenger cascades, including:

  • JAK-STAT pathway – the STAT protein family has been shown to have a key transduction role in cytokine receptor signalling; this pathway is initiated following the activation of PRLRs.[6] Although there have been 4 STAT proteins identified as transducer molecules of PRLR, STAT5 is recognised as the most important transducer of PRLR isoforms, with a role in inhibiting regulation of gene transcription.
  • Ras-Raf-MAPK – initiated by PRLR activation. Phosphotyrosine residues on PRLR act as binding sites for adapter proteins – these connect PRLR to the Ras/Raf/MAP kinase cascade
  • JAK-RUSH pathway [7][8]
  • PI3K/AKT/mTOR pathway[9]

Function

Expression of the PRLR protein is found within cells of the mammary glands[10] in accordance with its role in lactation, but also is the subject of attention for its diverse and emerging roles by its expression in adipose tissue,[11] pancreatic islet cell proliferation,[12] and immune responses.[13] The PRLR has been found to be essential for lobuloalveolar maturation of the mammary glands during pregnancy, as evidenced by the fact that PRLR knockout mice show severely impaired development of lobuloalveolar structures.[14][15] Disruption of PRLR signaling pathways have been linked to tumorigenesis and breast cancer development.[16]

Ligands

Agonists

Antagonists

Prolactin receptor antagonists such as Del1-9-G129R-hPRL have been developed.[18][19][20][21][22]

Dopamine agonists are currently the most common methods used for treating hyperprolactinemia. However, since dopamine agonists only negatively regulate prolactin production from the pituitary gland, a few studies have tried to develop prolactin receptor antagonists for potentially treating the dopamine-resistant local hyperprolactinemia.[18][23] Δ1–9-G129R-hPRL is one of the prolactin receptor antagonists been studied. Δ1–9-G129R-hPRL as a mutant (inactivated) form of prolactin which exerts its antagonist effect by competing with prolactin to bind with prolactin receptors; thereby, inhibiting the agonist effects of prolactin on prolactin receptors.[18] Besides molecular antagonists, antibodies can also potentially be used to inhibit prolactin receptor signaling. LFA102 is a monoclonal antibody that has been studied and tested for disrupting prolactin receptor's signaling in breast cancers and prostate cancers.[24] Although LFA102 has been proved sufficient to reduce prolactin receptor signaling based on in vitro and in vivo (mouse) studies, LFA102 likely has low effects on limiting tumor growth (breast and prostate cancer) as shown in phase I clinical trials.[24][25]

Prolactin receptor dysfunction

PRLR dysfunction has been seen to positively regulate the proliferation of malignant cells in breast cancer. Defects on prolactin receptor signalling can trigger tumour activity, rather than suppress. Signal control is monitored by a variety of genes, and the PRLR gene has been identified in the tissue of metastatic primary breast cancer cells.[26] The defect in the gene is thought to have built a resistance to chemotherapy, and has lost the ability to regulate the apoptosis of cells with mutated DNA.[27] This signalling defect then fails to promote the cellular differentiation, and promotes the upstream survival of the cancerous cells. In breast cancer, the survival of the breast epithelial cells resemble the malignant cells, characteristically known to have an increased proliferative rate.[28]

See also

References

  1. ↑ Brooks CL (August 2012). "Molecular mechanisms of prolactin and its receptor". review. Endocrine Reviews. 33 (4): 504–25. doi:10.1210/er.2011-1040. PMC 3410225. PMID 22577091.
  2. ↑ Brooks CL (August 2012). "Molecular mechanisms of prolactin and its receptor". Endocrine Reviews. 33 (4): 504–25. doi:10.1210/er.2011-1040. PMC 3410225. PMID 22577091.
  3. ↑ Minh Hung H, Dieu Hang T, Nguyen MT (June 2019). "Structural Investigation of Human Prolactin Receptor Transmembrane Domain Homodimerization in a Membrane Environment through Multiscale Simulations". The Journal of Physical Chemistry B. 123 (23): 4858–4866. doi:10.1021/acs.jpcb.9b01986. PMID 31099581. S2CID 157056703.
  4. ↑ Dandawate P, Kaushik G, Ghosh C, Standing D, Ali Sayed AA, Choudhury S, et al. (April 2020). "Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice". Gastroenterology. 158 (5): 1433–1449.e27. doi:10.1053/j.gastro.2019.11.279. PMC 7103550. PMID 31786131.
  5. ↑ Trott JF, Schennink A, Petrie WK, Manjarin R, VanKlompenberg MK, Hovey RC (May 2012). "Triennial Lactation Symposium: Prolactin: The multifaceted potentiator of mammary growth and function". Journal of Animal Science. 90 (5): 1674–86. doi:10.2527/jas.2011-4682. PMID 22205663.
  6. ↑ Freeman ME, Kanyicska B, Lerant A, Nagy G (October 2000). "Prolactin: structure, function, and regulation of secretion". Physiological Reviews. 80 (4): 1523–631. doi:10.1152/physrev.2000.80.4.1523. PMID 11015620.
  7. ↑ Helmer RA, Panchoo M, Dertien JS, Bhakta SM, Hewetson A, Chilton BS (August 2010). "Prolactin-induced Jak2 phosphorylation of RUSH: a key element in Jak/RUSH signaling". Molecular and Cellular Endocrinology. 325 (1–2): 143–9. doi:10.1016/j.mce.2010.05.010. PMC 2902710. PMID 20562009.
  8. ↑ Helmer RA, Dertien JS, Chilton BS (May 2011). "Prolactin induces Jak2 phosphorylation of RUSHY195". Molecular and Cellular Endocrinology. 338 (1–2): 79–83. doi:10.1016/j.mce.2011.03.009. PMID 21457752. S2CID 36530259.
  9. ↑ Clevenger CV, Furth PA, Hankinson SE, Schuler LA (February 2003). "The role of prolactin in mammary carcinoma". Endocrine Reviews. 24 (1): 1–27. doi:10.1210/er.2001-0036. PMC 1698952. PMID 12588805.
  10. ↑ Baran N, Kelly PA, Binart N (April 2002). "Characterization of a prolactin-regulated gene in reproductive tissues using the prolactin receptor knockout mouse model". primary. Biology of Reproduction. 66 (4): 1210–8. doi:10.1095/biolreprod66.4.1210. PMID 11906943. S2CID 22649010.
  11. ↑ Viengchareun S, Servel N, Fève B, Freemark M, Lombès M, Binart N (February 2008). "Prolactin receptor signaling is essential for perinatal brown adipocyte function: a role for insulin-like growth factor-2". primary. PLOS ONE. 3 (2): e1535. Bibcode:2008PLoSO...3.1535V. doi:10.1371/journal.pone.0001535. PMC 2212135. PMID 18253483.
  12. ↑ Arumugam R, Fleenor D, Freemark M (August 2014). "Knockdown of prolactin receptors in a pancreatic beta cell line: effects on DNA synthesis, apoptosis, and gene expression". primary. Endocrine. 46 (3): 568–76. doi:10.1007/s12020-013-0073-1. PMC 3984618. PMID 24114406.
  13. ↑ Dogusan Z, Book ML, Verdood P, Yu-Lee LY, Hooghe-Peters EL (September 2000). "Prolactin activates interferon regulatory factor-1 expression in normal lympho-hemopoietic cells". primary. European Cytokine Network. 11 (3): 435–42. PMID 11022129.
  14. ↑ Horseman ND (6 December 2012). Prolactin. Springer Science & Business Media. pp. 227–. ISBN 978-1-4615-1683-5.
  15. ↑ Bland KI, Copeland EM (9 September 2009). The Breast: Comprehensive Management of Benign and Malignant Diseases. Elsevier Health Sciences. pp. 44–45. ISBN 978-1-4377-1121-9.
  16. ↑ Nouhi Z, Chughtai N, Hartley S, Cocolakis E, Lebrun JJ, Ali S (February 2006). "Defining the role of prolactin as an invasion suppressor hormone in breast cancer cells". Cancer Research. 66 (3): 1824–32. doi:10.1158/0008-5472.CAN-05-2292. PMID 16452244.
  17. ↑ Bernichtein S, Kinet S, Jeay S, Llovera M, Madern D, Martial JA, et al. (September 2001). "S179D-human PRL, a pseudophosphorylated human PRL analog, is an agonist and not an antagonist". Endocrinology. 142 (9): 3950–63. doi:10.1210/endo.142.9.8369. PMID 11517174.
  18. 1 2 3 Goffin V, Touraine P, Culler MD, Kelly PA (October 2006). "Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia?". Nature Clinical Practice. Endocrinology & Metabolism. 2 (10): 571–81. doi:10.1038/ncpendmet0270. PMID 17024156. S2CID 21368033.
  19. ↑ Jomain JB, Tallet E, Broutin I, Hoos S, van Agthoven J, Ducruix A, et al. (November 2007). "Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL". The Journal of Biological Chemistry. 282 (45): 33118–31. doi:10.1074/jbc.M704364200. PMID 17785459.
  20. ↑ Jacobson EM, Hugo ER, Tuttle TR, Papoian R, Ben-Jonathan N (November 2010). "Unexploited therapies in breast and prostate cancer: blockade of the prolactin receptor". Trends in Endocrinology and Metabolism. 21 (11): 691–8. doi:10.1016/j.tem.2010.08.004. PMC 2967606. PMID 20846877.
  21. ↑ Hansen MJ, Olsen JG, Bernichtein S, O'Shea C, Sigurskjold BW, Goffin V, Kragelund BB (2011). "Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding". Journal of Molecular Recognition. 24 (4): 533–47. doi:10.1002/jmr.1064. PMID 20842635. S2CID 32885400.
  22. ↑ Ferraris J, Bernichtein S, Pisera D, Goffin V (2013). "Use of prolactin receptor antagonist to better understand prolactin regulation of pituitary homeostasis". Neuroendocrinology. 98 (3): 171–9. doi:10.1159/000354701. hdl:11336/8384. PMID 23969780.
  23. ↑ Karayazi Atıcı Ö, Govindrajan N, Lopetegui-González I, Shemanko CS (June 2021). "Prolactin: A hormone with diverse functions from mammary gland development to cancer metastasis". Seminars in Cell & Developmental Biology. 114: 159–170. doi:10.1016/j.semcdb.2020.10.005. PMID 33109441. S2CID 225100290.
  24. 1 2 Abramicheva PA, Smirnova OV (April 2019). "Prolactin Receptor Isoforms as the Basis of Tissue-Specific Action of Prolactin in the Norm and Pathology". Biochemistry. Biokhimiia. 84 (4): 329–345. doi:10.1134/S0006297919040011. PMID 31228925. S2CID 129945003.
  25. ↑ Goffin V, Touraine P (September 2015). "The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications". Expert Opinion on Therapeutic Targets. 19 (9): 1229–44. doi:10.1517/14728222.2015.1053209. PMID 26063597. S2CID 31029607.
  26. ↑ Bernard V, Young J, Binart N (June 2019). "Prolactin - a pleiotropic factor in health and disease". Nature Reviews. Endocrinology. 15 (6): 356–365. doi:10.1038/s41574-019-0194-6. PMID 30899100. S2CID 84846294.
  27. ↑ Shemanko CS (November 2016). "Prolactin receptor in breast cancer: marker for metastatic risk". Journal of Molecular Endocrinology. 57 (4): R153–R165. doi:10.1530/JME-16-0150. PMID 27658959.
  28. ↑ McHale K, Tomaszewski JE, Puthiyaveettil R, Livolsi VA, Clevenger CV (May 2008). "Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma". Modern Pathology. 21 (5): 565–71. doi:10.1038/modpathol.2008.7. PMID 18246042. S2CID 205199390.
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